The separation of enantiomers by means of salification with appropriate optically active counter-ions has been known for some time. However, the selection of the most suitable counter-ion and the reaction conditions, particularly the solvent and the temperature, allowing the attainment of good separation through the precipitation of one of the two diastereoisomeric salts, are difficult to predict.
(R)-(−)-3-(carbamoylmethyl)-5-methylhexanoic acid is an intermediate, useful in the preparation of biologically active molecules, such as for example pregabalin ((S)-(+)-3-(aminomethyl)-5-methylhexanoic acid).
EP0828704 describes the preparation of (R)-(−)-3-(carbamoylmethyl)-5-methylhexanoic acid by means of the salification of the acid racemate with (R)-(+)-α-phenylethylamine in chloroform, precipitation following cooling and subsequent acid hydrolysis of the salt formed between the R enantiomer of the acid and the optically active amine. The text of the patent indicates generically that the salification reaction/precipitation may proceed in an “organic solvent” but the examples normally report the use of chloroform, with the addition of a little ethanol. As is well known, chloroform is a solvent that cannot be used industrially since it is carcinogenic, even simply by inhalation.
Attempts to reproduce the described separation in a solvent other than chloroform have given negative results. In particular, crystallisation/precipitation has been attempted in solvents more suited to industrial use, such as ethyl acetate, cyclohexane, methanol, isopropanol, toluene, acetone, tetrahydrofuran and mixtures thereof, without attaining effective enantiomeric separation.
Hence, there remains a need to discover alternative synthetic pathways for the preparation of (R)-(−)-3-(carbamoylmethyl)-5-methylhexanoic acid.